Bridgehead Modifications of Englerin A Reduce TRPC4 Activity and Intravenous Toxicity but not Cell Growth Inhibition

Identifier:  imarina:9296648

Handle: https://hdl.handle.net/20.500.11797/imarina9296648

Authors:  Wu, Zhenhua; Suppo, Jean-Simon; Tumova, Sarka; Strope, Jonathan; Bravo, Fernando; Moy, Melody; Weinstein, Ethan S; Peer, Cody J; Figg, William D; Chain, William J; Echavarren, Antonio M; Beech, David J; Beutler, John A

Abstract:
Modifications at the bridgehead position of englerin A were made to explore the effects of variation at this site on the molecule for biological activity, as judged by the NCI 60 screen, in which englerin A is highly potent and selective for renal cancer cells. Replacement of the isopropyl group by other, larger substituents yielded compounds which displayed excellent selectivity and potency comparable to the natural product. Selected compounds were also evaluated for their effect on the ion channel TRPC4 as well as for intravenous toxicity in mice, and these had lower potency in both assays compared to englerin A.